Anti-cancer agents are often administered orally or by injection for transportation by the blood stream to the solid tumors in the liver, lung, breast, colon, rectum, prostate or brain. The anti-cancer agent must be transported by blood to the blood vessels of the tumor, pass the vessel wall, and go through the interstitium to reach the cancer cell. Unfortunately, in many cases, the agents are not as efficient as expected from results of toxicity tests with cultured malignant cancer cells. This is probably due to barriers to agent delivery in solid tumors (R. K. Jain, Sci. Am. 271(1994) 58). Thus, there is a need for improvement in anti-cancer agent delivery to solid tumors.
Solid malignant tumors comprise normal connective tissue cells in addition to malignant cancer cells within the tumor. The malignant cancer cells occupy only a part of the volume of the tumor and they are surrounded by the interstitium, i. e. a collagen rich extracellular matrix which can separate the cancer cells from the unevenly distributed blood vessels, which constitute approximately 1-10% of the tumor.
Rakesh K. Jain (ibid.) recognized inter alia that the abnormally high pressure in the interstitial matrix of a solid tumor can retard the passage of large molecules across vessel walls into the interstitial matrix and thus contribute to a low concentration of agent molecules frequently seen in the interstitial matrix of animal and human tumors growing in mice. He suggested among other things two pressure-related strategies to improve solid tumor therapy, namely injection of an agent mixed with a large amount of fluid directly into the center of a tumor to increase the pressure at the core of the tumor relative to the surrounding tumor tissue so that the agent would spread along the induced pressure gradient, and reduction of the interstitial pressure with the vasodilators pentoxifylline or high, near toxic doses, of the vitamin B3 derivative nicotinamide. Both agents are known to increase the oxygen supply in various tumors which is a benefit for radiation therapy.